The HIV viral coat protein ,gp120, is shed by microglia and has been reported to be directly toxic to neurons and to activate microglia, which may provide a self propelling cycle of microglial activation. However, while chemokine receptors have been named as critical to the process of GP120 activation, the mechanisms of GP120-induced microglial activation remains undefined. Recently, we have identified several factors that activate microglia through receptors involved in the phagocytosis of aggregated proteins (a synuclein, neuromelanin) or environmental particulates. These toxic compounds are recognized by phagocytosis/pattern recognition receptors on microglia, resulting in the activation of NADPH oxidase and the neurotoxic respiratory burst. Recently, we have shown that at nanomolar concentrations, gp120 is toxic to neurons only the presence of microglia and that gp120 produces extracellular and intracellular reactive oxygen species from microglia in response to LPS. Further, using neuron-glia cultures from mice lack a functional NADPH oxidase complex, we show that NADPH oxidase and extracellular superoxide plays a critical role in the microglia-mediated GP120-induced DA neurotoxicity. While it is not yet conclusive whether gp120 is being phagocytized and whether this is critical for microglial activation, further efforts in our laboratory will attempt to elucidate the mechanisms responsible for this phenomenon. Through identification of the mechanisms driving the neurodegeneration associated with AIDS-related dementia, we can hope to have better insight into the development of better therapeutic compounds.